Tuberculosis (TB) is the leading cause of death among people living with HIV (PLWH) worldwide. Despite recent scientific advances, significant gaps remain in our understanding of the immune mechanisms responsible for control and eradication of Mycobacterium tuberculosis (Mtb) infection. PLWH with latent TB infection (LTBI) have a ~10% annual risk of progressing to TB disease, however currently available tests for LTBI diagnosis have reduced sensitivity in this population and are not able to predict which latently infected individuals are at highest risk for developing TB for targeted preventive therapy. Emerging data from clinically relevant animal models suggest that LTBI and active TB represent a spectrum of immune responses and host pathology, with increasing metabolic changes and immune dysregulation during the transition to TB disease. We have identified unique serum metabolite and microRNA (miRNA) profiles that are able to discriminate between patients with TB and those with non-TB lung disease. However, these novel TB signatures have not been assessed prospectively to identify PLWH and HIV-negative persons with LTBI who are at increased risk for TB progression. In order to address this significant knowledge gap, in Aim 1 of the current research program, trainees will leverage the Indian and South African RePORT longitudinal biorepositories of household contacts of TB index cases to test the hypothesis that TB is a chronic inflammatory disease associated with profound changes in immune regulation and metabolism prior to the onset of clinical signs and symptoms. Another major barrier to global TB eradication efforts is the lengthy and complicated current anti-tubercular regimen, which is associated with medical nonadherence and the emergence of drug resistance. Recently, attention has focused on host-directed adjunctive therapies aimed at optimizing immune responses to the pathogen and improving lung damage. Lipid-laden macrophages (foam cells) are central to maintaining chronic TB infection by providing a favorable niche in which antimicrobial functions are down-regulated, and by inducing caseation and tissue damage. Recent work has shown that foam-cell-rich and necrotic areas of TB granulomas are particularly enriched in triglycerides. Mtb infection is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: a pro-lipogenic pathway involving protein kinase B and mTOR complex 1 (Akt/mTORC1), and an anti- lipogenic pathway involving AMP-activated protein kinase and the sirtuins (AMPK/SIRT). In Aim 2, trainees will use longitudinal clinical samples from RePORT study participants and experimental infections ex vivo to characterize: (i) the relationship between activation of these pathways and control of clinical Mtb infection, and the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo. The research aims will be integrated with a mentoring strategy for mentees that fosters development of high impact patient-oriented research with a pathway to independence.